Phenobarbital (PB) is a classic CAR activator and chronic PB treatment develops hepatocellular carcinoma in rodents. In an effort to decipher the signal mechanism by which PB indirectly activates CAR, PKC is now determined to be the protein kinase that phosphorylates threonine 38 of human CAR. This phosphorylation inactivates trans-activation activity of CAR and represses PB response nuclear translocation of CAR. Drug activation of PXR is known to often cause bone diseases similar to those observed in vitamin D3 deficiency. PXR is now found to inhibit vitamin D3-VDR-mediated induction of the CYP24A1 gene by locking the co-repressor SMRT onto the VDR on the CYP24A1 promoter. It is also found that PXR directly interacts with the insulin response transcription factor FoxA2, inhibiting its binding to target promoters, repressing hepatic -oxidation and ketogenesis, while inducing hepatic lipogenesis via a as yet unknown mechanism.